Carbamazepine, or 5H-dibenz[b,f]azepine-5-carboxamide, is a widely used anticonvulsant agent having the structural formula ##STR1## It is available in the U.S. as Tegretol.RTM. brand chewable tablets of 100 mg, tablets of 200 mg and suspension of 100 mg/5 mL, intended for oral administration as an anticonvulsant or as a specific analgesic for trigeminal neuralgia. Recommended maintenance dosage levels in adults and children over 12 years of age are 800-1200 mg daily, although up to 1600 mg daily have been used in adults. In children of 6 to 12 years of age, the maintenance dosage level is usually 400-800 mg daily.
For complex partial seizures (temporal lobe, psychomotor), carbamazepine is considered the anticonvulsant drug of choice. It is also of proven efficacy in the treatment of generalized tonic-clonic seizures (grand mal). In addition, carbamazepine has been used in treating simple partial (focal, Jacksonian) seizures and in patients with mixed seizure patterns which include the above, or other partial or generalized seizures. It is not used in the treatment of absence seizures (petit mal).
In addition to its proven effectiveness, carbamazepine has, in many respects, a more favorable profile in terms of the incidence and severity of side-effects than other anticonvulsants. Thus, carbamazepine is less sedating and causes less intellectual function impairment than other antiepileptic drugs such as phenobarbital, primidone and phenytoin. Furthermore, carbamazepine does not precipitate gingival hypertropy, hirsutism, acne or other undesired effects associated with phenytoin. These attributes have helped to make carbamazepine the drug of choice in women and children.
Nevertheless, carbamazepine usage is not without its difficulties. The drug should, in general, not be used in combination with other drugs because of dangerous drug interactions. Therapeutic plasma levels of carbamazine range from about 4 to 10 .mu.g/mL, but adverse effects are generally encountered in about 50% of patients with serum carbamazepine levels of 8.5 to 10 .mu.g/mL. Thus, the therapeutic index is not large. Such adverse effects as diplopia, dizziness, drowsiness and ataxia occur above 6 .mu.g/mL, and nystagmus may occur at serum levels below the therapeutic range. Anorexia, nausea, rash (including Stevens-Johnson syndrome), edema, aplastic anemia, agranulocytosis, thrombocytopenia and transient leukopenia may also occur. The most severe effects are those which have been observed in the hemopoietic system, the skin and the cardiovascular system, some of which have resulted in fatalities.
Carbamazepine has been used as an anticonvulsant agent for over 20 years. During that time, a number of workers have studied the absorption characteristics, including the bioavailability, of carbamazepine from various formulations thereof. From Morselli, Chapter 33 in Antiepileptic Druge, Third Edition, ed. R. Levy et al, Raven Press, Ltd., N.Y., 1989, 473-490, and references cited therein, it appears to be widely recognized that the oral absorption of carbamazepine is slow and somewhat erratic. It is equally widely recognized, however, that oral absorption is adequate; see, for example, The Pharmacological Basis of Therapeutics, ed. Louis S. Goodman and Alfred Gilman, fifth edition, MacMillan Publishing Co., Inc., N.Y., 1975, page 211.
Relative total bioavailabilities reported for various carbamazepine formulations appear to be relatively constant, although rates of absorption may differ.
Monaco et al, J. Int. Med. Res. 12 (1984), 108-113, found no difference in plasma levels when carbamazepine was given to epileptic patients in 200 or 400 mg tablets, and indicated that their data supported the similar bioavailability of 200 mg and 400 mg carbamazepine tablets during chronic administration to epileptic patients.
Eadie et al, The Medical Journal of Australia, Vol. 146, Mar. 16, 1987, 313-316, found differences in absorption rates between tablets available in Australia in 1977 and those available since 1980, but no significant difference in total bioavailability (area under the curve). The authors attributed any discrepancies between earlier Australian reports and European data relating to bioavailability to a reduced absorption rate of Australian carbamazepine before 1980, and noted that the non-Australian workers had not questioned the bioavailability of the drug in the preparations they tested, although no intravenous preparation was available for comparison.
The relative bioavailability of an extemporaneous carbamazepine oral suspension relative to that of the tablet used in its manufacture was reported by Bloomer et al, Chemical Pharmacy, Vol. 6, Aug. 1987, 646-649. Although the mean time to maximum concentration was significantly shorter after suspension than after tablet administration, there was no significant difference in the extent of absorption. Mean (.+-.S.D.) bioavailability of the suspension relative to the tablet was 94.46% .+-. 20.42. The authors indicated these findings to be similar to those of similar studies of the commercial carbamazepine oral suspension.
Maas et al, Therapeutic Drug Monitoring 9, 28-33 (1987), have described a comparative bioavailability study of carbamazepine tablets and a chewable tablet formulation. Although the authors noted that carbamazepine "is relatively water insoluble and oral absorption is erratic, with great variability in absorption rates noted between individuals and between various oral formulations", no significant differences in the bioavailability between carbamazepine 200 mg tablets and an equivalent dose of chewable tablets were found in their study. Statistically significant differences in peak plasma concentrations were found but the clinical significance was deemed minimal and the two types of tablets were concluded to be interchangeable.
Graves et al, Epilepsia, 24 (1983), 604-608, studied the bioavailability of rectally administered carbamazepine suspension in dogs. Doses of 20 mg/kg were given to dogs as oral tablet, oral suspension and rectal suspension. No significant difference in total absorption was noted between the oral and rectal suspensions. Rectal administration was found to produce a prolonged, though complete, absorption profile relative to the oral suspension. Neuvonen et al, Br. J. clin. Pharmac. 24 (1987), 839-841, in studies of healthy human subjects, made essentially the same finding, i.e. that absorption was significantly slower after the rectal than after the oral route, but the total bioavailability was similar.
Because of the lack of an injectable formulation for carbamazepine, there has not been precise information relating to the drug's absolute bioavailability. Values estimated from studies using .sup.14 C-labeled carbamazepine have ranged from 75% to 85%. See Morselli, Chapter 33 in Antiepileptic Drugs, Third Edition, ed. R. Levy et al, Raven Press, Ltd., N.Y., 1989, 473-490, particularly page 474 and the Faigle et al reference cited therein. Very recently, Gerardin et al, in Epilepsia, 31(3), 1990, 334-338, have reported on the absolute bioavailability of carbamazepine after oral administration of a 2% syrup. Healthy male volunteers were given 100 mg of carbamazepine as a intravenous infusion and 100 mg of 15N-labeled carbamazepine as a 2% oral suspension, concomitantly. Comparison of the areas under the plasma curves (AUC) obtained by the two routes of administration showed the bioavailability of carbamazepine from the oral suspension to be equivalent to its bioavailability when administered intravenously. Absolute bioavailability of carbamazepine administered as the oral suspension was calculated as 102.3% and 100.1% for subjects 1 and 2, respectively.
Thus, the consensus in the art has been to the effect that the total oral bioavailability of carbamazepine is highly acceptable and leaves little, if any, room for improvement. The most improvement in oral bioavailability possible based on the carbamazepine literature would appear to be approximately 18-33%. a very modest increase which, even if attainable, would likely not warrant reformulation of existing compositions.
Cyclodextrins are cyclic oligosaccharides. The most common cyclodextrins are .alpha.-cyclodextrin, which is composed of a ring of six glucose residues; .beta.-cyclodextrin, which is composed of a ring of seven glucose residues; and .gamma.-cyclodextrin, which is composed of a ring of eight glucose units. The inside cavity of a cyclodextrin is lipophilic, while the outside of the cyclodextrin is hydrophilic; this combination of properties has led to widespread study of the natural cyclodextrins, particularly in connection with pharmaceuticals, and many inclusion complexes have been reported. .beta.-Cyclodextrin has been of special interest because of its cavity size, but its relatively low aqueous solubility (about 1.8% w/v at 25.degree. C.) and attendant nephrotoxicity have limited its use in the pharmaceutical field.
Attempts to modify the properties of the natural cyclodextrins have resulted in the development of heptakis (2,6-di-O-methyl)-.beta.-cyclodextrin, heptakis (2,3,6-tri-O-methyl)-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, .beta.-cyclodextrin-epichlorohydrin polymer and others. For a comprehensive review of cyclodextrins and their use in pharmaceutical research, see Pitha et al, in Controlled Drug Delivery, ed. S.D. Bruck, Vol. I, CRC Press, Boca Raton, Fla., 125-148 (1983). For an even more recent overview, see Uekama et al, in CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3 (1), 1-40 (1987); Uekama, in Topics in Pharmaceutical Sciences 1987, eds. D. D. Breimer and P. Speiser, Elsevier Science Publishers B.V. (Biomedical Division), 1987, 181-194; and Pagington, Chemistry in Britain, May 1987, 455-458.
Inclusion complexes of .alpha.-, .beta.- or .gamma.-cyclodextrin or their mixtures with a variety of drugs have been described by numerous parties and various advantages have been attributed to the complexes. These descriptions include those documents summarized in Bodor U.S. Pat. Nos. 4,983,586 and 5,024,998, incorporated by reference herein in their entireties and relied upon.
Inclusion complexes of 2,6-di-0-methyl-.beta.-cyclodextrin with dibenzo[bd]pyran derivatives and salts having analgesic, antemetic and narcosis-potentiating activities have been described in Nogradi et al U.S. Pat. No. 4,599,327; increased water solubility and thus improved biological activity have been claimed for the complexes. A review of the pharmaceutical applications of such methylated cyclodextrins has been published by Uekama, Pharm. Int., Mar. 1985, 61-65; see also Pitha, Journal of Inclusion Phenomena 2, 477-485 (1984).
Cyclodextrin polymer has been reported by Fenyvesi et al, Chem. Pharm. Bull. 32 (2), 665-669 (1984) to improve the dissolution of furosemide. Improvements in the dissolution and absorption of phenytoin using a water-soluble .beta.-cyclodextrin epichlorohydrin polymer have been described by Uekama et al, International Journal of Pharmaceutics, 23, 35-42 (1985).
Hydroxypropyl-.beta.-cyclodextrin and its preparation by propylene oxide addition to .beta.-cyclodextrin were described in Gramera et al U.S. Pat. No. 3,459,731 approximately 20 years ago. (Gramera et al also described the analogous preparation of hydroxyethyl-.beta.-cyclodextrin by ethylene oxide reaction with .beta.-cyclodextrin.) Much more recently recently, Pitha and coworkers have described the improved preparation of this cyclodextrin derivative and its effects on the dissolution of various drug molecules. See Pitha U.S. Pat. No. 4,596,795, dated Jun. 24, 1986. Success with other cyclodextrins, including poly-.gamma.-cyclodextrin and hydroxypropyl-.gamma.-cyclodextrin, have also been noted in the Pitha patent. See also Pitha et al, J. Pharm. Sci., Vol. 74, No. 9, Sep. 1985, 987-990, concerning the same and related studies.
The improved, optimized preparation and purification of hydroxypropyl-.beta.-cyclodextrin has been described by Pitha et al, International Journal of Pharmaceutics, 29, 73-82 (1986). In the same publication, the authors have described increased water solubility for 32 drugs in concentrated (40 to 50%) aqueous solutions of hydroxypropyl-.beta.-cyclodextrin. The authors indicated this to be an extension of their earlier work with hydroxypropyl-.beta.-cyclodextrin, which was previously found effective for oral administration of the sex hormones to humans. Their later work reported in Pitha et al, International Journal of Pharmaceutics, 29, 73-82 (1986), has also been described in Pitha U.S. Pat. No. 4,727,064, dated Feb. 23, 1988. That patent claims a composition containing an amorphous complex of cyclodextrin and a drug, and a method of producing a stabilizing amorphous complex of a drug and a mixture of cyclodextrins comprising (1) dissolving an intrinsically amorphous mixture of cyclodextrin derivatives which are water soluble and capable of forming inclusion complexes with drugs in water; and (2) solubilizing lipophilic drugs into aqueous media to form a solution and form a solubilized drug/cyclodextrin complex. The patent describes the preparation of various substituted amorphous cyclodextrins, including hydroxypropyl-.beta.-cyclodextrin and hydroxypropyl-.gamma.-cyclodextrin, the latter by analogous condensation of propylene oxide and .gamma.-cyclodextrin.
Uekama et al, CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3 (1), 1-40 (1987), have described the characteristics of various cyclodextrins, including hydroxypropyl-.beta.-cyclodextrin. The authors have presented data showing improved solubilization in water in the presence of 15 mg/mL of hydroxypropyl-.beta.-cyclodextrin for the drugs carmofur, diazepam, digitoxin, digoxin, flurbiprofen, indomethacin, isosorbide dinitrate, phenytoin, prednisolone, progesterone and testosterone. The authors have further indicated that parenteral administration of large doses of cyclodextrins should be avoided, but that ".gamma.-cyclodextrin and hydroxypropyl-.beta.-cyclodextrin seem to be useful in drug solubilization for injections and liquid preparations used for mucous membranes."
JANSSEN PHARMACEUTICAL N.V.'s International Patent Application No. PCT/EP84/00417, published under International Publication No. W085/02767 on Jul. 4, 1985, has described pharmaceutical compositions comprising inclusion compounds of drugs, which are unstable or only sparingly soluble in water, with partially etherified .beta.-cyclodextrin derivatives having hydroxyalkyl and optionally additional alkyl groups. Among the cyclodextrin derivatives contemplated is hydroxypropyl-.beta.-cyclodextrin, while the drugs include nonsteroidal anti-rheumatic agents, steroids, cardiac glycosides and derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole and triazole.
The preparation of amorphous water-soluble cyclodextrin derivatives, including 2-hydroxyethyl-.beta.-cyclodextrin, 3-hydroxypropyl-.beta.-cyclodextrin and 2-hydroxypropyl-.gamma.-cyclodextrin, is described by Irie et al, Pharmaceutical Research, Vol. 5, No. 11, 1988, 713-717. That report also addresses the distribution of the substituents among the glucose residues of the cyclodextrin ring.
A pharmaceutical evaluation of hydroxyalkyl ethers of .beta.-cyclodextrin has been reported by Yoshida et al, International Journal of Pharmaceutics 46, 1988, 217-222. Aqueous solubilities, surface activities, hemolytic activity and local irritancy are reported. The data suggest that hydroxyalkyl-.beta.-cyclodextrins overcome many of the undesirable characteristics of .beta.-cyclodextrin usage in pharmaceuticals.
JANSSEN PHARMACEUTICA N.V.'s European Patent Application No. 86200334.0, published under EPO Publication No 0197571 on Oct. 15, 1986, describes .gamma.-cyclodextrin derivatives which are .gamma.-cyclodextrin substituted with C.sub.1 -C.sub.6 alkyl, hydroxy C.sub.1 -C.sub.6 alkyl, carboxy C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 alkyloxycarbonyl C.sub.1 -C.sub.6 alkyl or mixed ethers thereof. Among the specific derivatives named are hydroxypropyl-.gamma.-cyclodextrin and hydroxyethyl-.gamma.-cyclodextrin. Compositions comprising the cyclodextrin derivatives and a drug are also described. See also corresponding Muller U.S. Pat. No. 4,764,604, dated Aug. 16, 1988.
Uekama, in Topics in Pharmaceutical Sciences 1987, eds. D. D. Breimer and P. Speiser, Elsevier Science Publishers B.V. (Biomedical Division), 1987, 181-194, has described the effects on bio-pharmaceutical properties of maltosyl and glucosyl cyclodextrin derivatives, as well as hydroxypropyl and other hydrophilic cyclodextrin derivatives, including enhanced drug absorption. The mechanism of enhancing drug absorption is described and the apparent stability constants for inclusion complexes of various drugs with .beta.-cyclodextrin, dimethyl-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin and maltosyl-.beta.-cyclodextrin are given. Drugs studied with these cyclodextrins include benoxaprofen, biphenyl acetic acid, carmofur, clofibrate, chlorpromazine, diazepam, diclofenac, digitoxin, digoxin, ethyl 4-biphenyl acetate, flurbiprofen, isosorbide dinitrate, indomethacin, menadione, nimodipine, nisoldipine, phenytoin, prednisolone, progesterone, prostacyclin, various prostaglandins (E.sub.1, E.sub.2, A.sub.1, A.sub.2), protriptyline, spironolactone and testosterone.
Bodor U.S. Pat. Nos. 5,002,935, issued Mar. 26, 1991, and 5,017,566, issued May 21, 1991, relate to stabilizing the reduced, dihydropyridine forms of dihydropyridine.revreaction.pyridinium salt redox systems for brain-targeted drug delivery by complexation with cyclodextrin selected from the group consisting of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .beta.- and .gamma.-cyclodextrins. The complexes also provide a means for increasing the ratio of initial brain to lung concentrations of drug, leading to decreased toxicity. In selected instances, improved water solubilities are noted as well.
Bodor U.S. Pat. Nos. 4,983,586, issued Jan. 8, 1991, and 5,024,998, issued Jun. 18, 1991, relate to pharmaceutical formulations for parenteral use. Aqueous parenteral solutions of drugs which are insoluble or only sparingly soluble in water and/or which are unstable in water, combined with cyclodextrin selected from the group consisting of hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of .beta.- and .gamma.-cyclodextrins, provide a means for alleviating problems associated with drug precipitation at the injection site and/or in the lungs or other organs following parenteral administration. The parenteral solutions contain from about 20% to about 50% of the selected cyclodextrin(s). The drugs may be the dihydropyridine forms of dihydropyridine.revreaction. pyridinium salt redox systems or other poorly soluble or unstable drugs of various types, including anticonvulsants.
In related literature, the present inventor and his coworkers have very recently described, in Brewster et al, J. Pharm. Sci., Vol. 80, No. 4, Apr. 1991, 380-383, the development of aqueous parenteral formulation for carbamazepine through the use of modified cyclodextrins. The Brewster et al publication is incorporated by reference herein in its entirety and relied upon. In that publication, the authors note that no intravenous formulation of carbamazepine is currently available, due to the drug's extremely poor water solubility. This makes monotherapy, which is the method of choice in treating convulsive disorders, not possible with carbamazepine when a parenteral form is required, e.g. in pediatric and emergency medicine and in managing the epileptic surgical patient. Accordingly, the ability of various cyclodextrins to enhance the aqueous solubility of carbamazepine was examined in the Brewster et al publication. Dimethyl-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, hydroxyethyl-.beta.-cyclodextrin, .gamma.-cyclodextrin and hydroxypropyl-.gamma.-cyclodextrin were all found to significantly enhance the water solubility of carbamazepine. Further testing of carbamazepine solubilized in hydroxypropyl-.beta.-cyclodextrin showed good stability and potent anticonvulsant effects in both mice and rats when administered intravenously.
CIBA-GEIGY AG's European Patent Publication No. 0435826, published Jul. 3, 1991, describes an aqueous intravenous solution of carbamazepine or oxcarbazepine for use in treating status epilepticus. The aqueous solubility of the drug is enhanced by means of a hydrophilic C.sub.1 -C.sub.6 alkyl, carboxy C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxycarbonyl C.sub.1 -C.sub.6 alkyl and/or hydroxy C.sub.2 -C.sub.6 alkyl .gamma.-cyclodextrin derivative. 2-Hydroxypropyl-, 3-hydroxypropyl- and 2-hydroxyethyl-.gamma.-cyclodextrin are specifically disclosed.
CIBA-GEIGY AG's European Patent Publication No. 0400609, published Dec. 5, 1990, describes an aqueous intravenous solution of carbamazepine in which the drug's aqueous solubility is enhanced by means of C.sub.1 -C.sub.4 alkyl and/or hydroxy-C.sub.2 -C.sub.4 alkyl derivatives of .beta.-cyclodextrin. 2-Hydroxypropyl-.beta.-cyclodextrin and 3-hydroxypropyl-.beta.-cyclodextrin are specifically disclosed.
The Brewster et al publication and that of EP 0435826 and EP 0400609 are limited to parenteral formulations and are, moreover, less than one year prior to the filing date of the present application. At any rate, it has not been recognized by others that the available commercial oral formulations of carbamazepine could be substantially and indeed surprisingly improved upon, in terms of oral bioavailability, through the use of selected cyclodextrin derivatives.